US Patent 9,796,721: Claim Scope, Remibrutinib Crystal Form, Exclusivity and Patent Landscape
US Patent 9,796,721 protects a specific anhydrous crystalline form of remibrutinib, a covalent Bruton’s tyrosine kinase inhibitor formerly identified as LOU064. The patent does not broadly claim remibrutinib as a chemical entity. Its principal protection is directed to a defined polymorph identified by an X-ray powder diffraction pattern. Dependent claims extend protection to pharmaceutical compositions containing that polymorph, compositions with specified extragranular acidulants, and use of the composition for treating selected B-cell malignancies.
The patent is commercially important if remibrutinib is developed or marketed in the claimed solid form. A competing product using a different polymorph, amorphous material, salt, or formulation may avoid literal infringement, although equivalence, conversion during manufacture, and regulatory product-comparison issues remain relevant.
What drug and crystal form does US Patent 9,796,721 protect?
The claimed active ingredient is remibrutinib, chemically identified in the patent as:
(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide.
The patent protects a crystalline, anhydrous form of this molecule. The solid form is defined principally through Cu-Kα X-ray powder diffraction peaks rather than through a separate structural formula or a generic polymorph description.
| Patent element |
Scope |
| Active ingredient |
Remibrutinib |
| Solid form |
A specified crystalline form |
| Hydration state |
Claimed as crystalline anhydrate in claim 5 |
| Primary analytical method |
Reflection XRPD |
| Primary peak set |
6.4°, 8.6°, 10.5°, 11.6° and 15.7° 2θ, each ±0.2° |
| Composition protection |
Pharmaceutical composition containing the claimed crystal |
| Formulation limitation |
Optional extragranular acidulant |
| Therapeutic use |
BTK inhibition and selected hyperproliferative diseases |
| Key assignee context |
Novartis group patent estate associated with remibrutinib |
The patent specification and claims should control any infringement or validity analysis. Patent databases identify the document as US9796721B2, titled “Crystalline forms of” the remibrutinib compound. The issued patent claims are the relevant legal instrument, while the prosecution history may affect interpretation of the XRPD and formulation limitations (Google Patents, n.d.; U.S. Patent and Trademark Office, n.d.).
How many independent inventions are claimed?
The issued claims contain three practical protection layers:
- A crystal-form layer.
- A pharmaceutical-composition layer.
- A method-of-treatment layer.
Claim 1 is the principal crystal-form claim. Claim 8 is the principal composition claim. Claim 12 is the principal therapeutic-use claim, but it depends on claim 8 and therefore incorporates the composition and crystal-form limitations.
Claim hierarchy
| Claim |
Subject matter |
Legal effect |
| 1 |
Crystal form identified by five XRPD peaks |
Broadest crystal-form claim |
| 2 |
Claim 1 plus six additional XRPD peaks |
Narrower fingerprint |
| 3 |
Claim 2 plus one or more additional peaks from a long list |
Alternative narrower peak subset |
| 4 |
Claim 2 plus the full additional peak set |
Most analytically specific XRPD claim |
| 5 |
Claim 2 crystal form characterized as an anhydrate |
Adds hydration-state limitation |
| 6 |
XRPD peaks measured using Cu-Kα radiation |
Measurement limitation |
| 7 |
XRPD peaks measured under specified Bruker D8 conditions |
Instrument and test-condition limitation |
| 8 |
Composition containing the crystal form |
Product composition claim |
| 9 |
Composition with an extragranular acidulant |
Formulation limitation |
| 10 |
Specified acidulants or combinations |
Specific excipient alternatives |
| 11 |
Alginic acid or sodium/potassium alginate |
Narrower acidulant subset |
| 12 |
Administration of claim 8 composition to inhibit BTK |
Method claim |
| 13 |
Treatment of a hyperproliferative disease |
Disease limitation |
| 14 |
Chronic lymphocytic leukemia |
Disease-specific claim |
| 15 |
Small lymphocytic lymphoma |
Disease-specific claim |
| 16 |
Mantle cell lymphoma |
Disease-specific claim |
| 17 |
Waldenström’s macroglobulinemia |
Disease-specific claim |
Claim 3 contains a drafting anomaly in the supplied text: “33.4°±0.2° 2θ°±0.2° 2θ.” That appears to be a typographical duplication. The issued patent and certified prosecution record should be used to determine the authoritative wording.
What is the scope of claim 1?
Claim 1 requires a crystal form of remibrutinib having all five listed XRPD reflections:
- 6.4° ± 0.2° 2θ
- 8.6° ± 0.2° 2θ
- 10.5° ± 0.2° 2θ
- 11.6° ± 0.2° 2θ
- 15.7° ± 0.2° 2θ
A product would generally fall within claim 1 if testing demonstrates that its remibrutinib solid contains the claimed crystalline phase and exhibits each required reflection within the stated tolerance.
The claim does not expressly require:
- a particular particle size;
- a particular tablet strength;
- a particular excipient;
- a specific manufacturing process;
- a specific solvent of crystallization;
- a specific degree of purity;
- a specific therapeutic indication; or
- a particular dosage form.
The claim is therefore narrow in chemical-solid-state identity but broad in commercial presentation. It can potentially cover the same crystal form in a tablet, capsule, granule, suspension precursor, or bulk active pharmaceutical ingredient.
How do claims 2 through 7 narrow the patent?
Claims 2 through 7 create evidentiary and fallback positions around the basic polymorph.
Claim 2 requires the five claim 1 peaks plus six additional reflections at 10.9°, 12.7°, 13.4°, 14.3°, 14.9° and 18.2° 2θ. This provides a more detailed diffraction fingerprint.
Claim 3 requires one or more reflections from a long list of additional peaks. Because it uses “one or more,” it is less restrictive than claim 4, assuming the dependency and claim construction are read in their ordinary manner.
Claim 4 requires the entire additional peak set. It is the most detailed XRPD claim and may be more difficult to prove against a sample with variable crystallinity, preferred orientation, impurities, or different test conditions.
Claim 5 requires the form to be an anhydrate. This limitation can materially narrow the claim because a hydrate, solvate, co-crystal, salt, or amorphous form may not satisfy the anhydrate requirement.
Claims 6 and 7 address measurement conditions. Claim 6 specifies Cu-Kα radiation. Claim 7 identifies a Bruker D8 Advance diffractometer, LynxEye detector, Bragg-Brentano geometry, 40 kV voltage, 40 mA current, 0.02° 2θ step size, 0.5 revolutions per second sample rotation and 37-second step time.
The instrument-specific language may create proof issues. A defendant may argue that its material should be assessed under the claimed method, while the patent owner may rely on claim construction, the specification, and equivalent analytical conditions to establish the same crystal form.
What formulations are protected by US Patent 9,796,721?
Claim 8 covers a pharmaceutical composition comprising the claimed remibrutinib crystal form and at least one pharmaceutically acceptable excipient.
Claims 9 through 11 add an extragranular acidulant. The listed materials include:
- fumaric acid;
- succinic acid;
- D-tartaric acid;
- L-tartaric acid;
- racemic tartaric acid;
- ascorbic acid;
- isoascorbic acid;
- alginic acid;
- sodium or potassium alginate;
- Protacid F 120 NM;
- Protacid AR 1112; and
- Carbopol 971P.
The use of “extragranular” is commercially meaningful. It distinguishes the acidulant’s location in the dosage-form manufacturing process from an acidulant incorporated inside granules. A formulation can contain the claimed crystal and an acidulant but avoid claims 9 through 11 if the acidulant is not extragranular. It may still infringe claim 8.
The composition claims may be relevant to commercial tablets even if the active pharmaceutical ingredient is manufactured by a third party. In a finished-product case, testing would focus on whether the tablet contains the claimed crystal form, not merely whether it contains remibrutinib.
What therapeutic uses are covered?
Claim 12 covers administering the claim 8 composition to a human in an amount effective to inhibit BTK activity. Claims 13 through 17 limit the disease context to hyperproliferative disease and then identify:
- chronic lymphocytic leukemia;
- small lymphocytic lymphoma;
- mantle cell lymphoma; and
- Waldenström’s macroglobulinemia.
These claims do not cover every remibrutinib use independently. They depend on the claim 8 composition. A method using a different crystal form or a composition lacking the claim 8 limitations would not literally satisfy claim 12.
The therapeutic claims are also distinct from any later regulatory indication for remibrutinib. Patent claim scope depends on the issued claim language, while FDA labeling depends on the approved application and indication.
When does US Patent 9,796,721 lose exclusivity?
US Patent 9,796,721 has a 20-year patent-term framework measured from the relevant nonprovisional or international filing date, subject to patent-term adjustment and any applicable patent-term extension.
A precise expiration date requires review of the official USPTO patent record, including:
- the earliest effective nonprovisional filing date;
- any PCT national-stage relationship;
- patent-term adjustment;
- terminal disclaimers; and
- any patent-term extension.
The patent issued on October 24, 2017. Its issue date does not determine expiration. The controlling date is the statutory patent term calculated from the relevant filing history, not the grant date (U.S. Patent and Trademark Office, n.d.).
Because remibrutinib has not been approved by FDA as a marketed U.S. drug in the records generally associated with this patent, there is no established FDA patent-term-extension period linked to an approved remibrutinib product. Patent term and regulatory exclusivity should be analyzed separately.
What is the Orange Book status of remibrutinib and this patent?
The Orange Book lists patents associated with approved drug products. Remibrutinib is not generally identified as an FDA-approved product with an Orange Book listing. Accordingly, US Patent 9,796,721 should not be treated as an Orange Book-listed patent for an approved remibrutinib product unless a later FDA submission changes that status.
The practical consequences are significant:
- There is no conventional ANDA-based Paragraph IV pathway against an unapproved reference product.
- A generic applicant cannot use ordinary ANDA substitution before FDA approval of a reference product.
- A future approved remibrutinib product could generate Orange Book listings if the patent claims the drug substance, formulation, composition, or approved method of use.
- The patent may still be asserted independently under 35 U.S.C. § 271, including against commercial manufacture, importation, sale, or use.
FDA Orange Book status is therefore a regulatory question, not a complete measure of enforceability or commercial relevance (U.S. Food and Drug Administration, n.d.).
Are there Paragraph IV challenges or patent litigation?
No established public Paragraph IV challenge or Hatch-Waxman litigation against US Patent 9,796,721 is identified in the standard regulatory context because remibrutinib has not had the conventional approved-reference-product framework that generates ANDA litigation.
The absence of a Paragraph IV case does not establish that the patent is valid, enforceable, or unchallengeable. Potential challenges could include:
- anticipation by a prior disclosure of the same polymorph;
- obviousness based on known remibrutinib forms and routine crystallization;
- inadequate written description of the full peak set;
- enablement issues involving production and reproducibility;
- indefiniteness of XRPD peak tolerances;
- failure to distinguish the claimed form from mixtures or partially crystalline material; and
- noninfringement based on a different polymorph, hydrate, solvate, or amorphous form.
A definitive litigation-status conclusion requires a current PACER, USPTO Patent Center and FDA records review. The patent should therefore be treated as an issued but untested solid-form right absent a reported final validity judgment.
How strong is the patent estate for this crystal form?
The patent is strongest against a company that commercializes the same anhydrous polymorph. It is weaker against a competitor that can develop and control a different solid form.
| Risk category |
Assessment |
| Same claimed polymorph |
High infringement risk |
| Same polymorph in a different tablet |
High, if claim 8 is met |
| Same polymorph with non-listed excipients |
Claim 8 risk remains |
| Same polymorph with listed extragranular acidulant |
High claims 9-11 risk |
| Hydrate or solvate |
Potentially lower, subject to claim construction |
| Amorphous remibrutinib |
Generally outside literal crystal-form claims |
| Different polymorph |
Potential design-around route |
| Chemical synthesis producing claimed form at isolation |
Potential process and product exposure |
| Bulk API imported into the United States |
Potential section 271 importation risk |
| Method using a non-claim-8 composition |
Lower risk under claims 12-17 |
The commercial strength of the patent depends on whether the claimed form is the selected development form, whether conversion between forms occurs during manufacturing or storage, and whether the product’s solid-state specification can be tested reliably.
What manufacturing and intellectual-property barriers exist?
The patent creates several barriers beyond the XRPD claim itself.
First, a competitor must identify a stable alternative form that can be manufactured at scale. A theoretical design-around is less useful if the alternative has poor dissolution, stability, compressibility, hygroscopicity or bioavailability.
Second, manufacturing conditions may unintentionally produce the patented form. Solvent, temperature, seeding, drying and milling conditions can affect polymorphic conversion. A process that begins with a different form but converts to the patented anhydrate before release may create product-infringement exposure.
Third, regulatory comparability may constrain a formulation strategy. A different polymorph may require new solid-state, bioequivalence, stability and manufacturing data. If remibrutinib is approved using the patented crystal, a later applicant may face both patent risk and regulatory development cost.
Fourth, the crystal patent may operate alongside separate patents covering the remibrutinib molecule, synthetic intermediates, therapeutic uses, formulations, salts, or manufacturing processes. This patent should not be treated as the complete remibrutinib estate.
How does this patent compare with a chemical-compound patent?
A compound patent generally covers the molecular structure across physical forms. A polymorph patent covers a narrower physical form but can be highly effective against the commercial product if that form is used.
| Issue |
Compound patent |
US 9,796,721 |
| Core subject |
Remibrutinib molecule |
Specific remibrutinib crystal |
| Breadth |
Broad chemical coverage |
Narrow solid-state coverage |
| Design-around |
Difficult if molecule is essential |
More feasible through alternate forms |
| Infringement evidence |
Chemical identity |
XRPD and solid-state analysis |
| Product relevance |
Usually high |
High if marketed form matches |
| Formulation dependence |
Usually limited |
Claims 8-11 directly address formulations |
| Regulatory significance |
Often Orange Book-relevant if approved |
Relevant if listed or tied to approved product |
| Validity issues |
Prior chemical disclosure, obviousness |
Polymorph anticipation, obviousness, reproducibility |
What generic or biosimilar entry risks exist?
Remibrutinib is a small molecule, not a biologic. Biosimilar procedures under the Public Health Service Act and the Purple Book are not applicable. Any future generic pathway would ordinarily be an ANDA or, depending on the product and regulatory circumstances, a 505(b)(2) application.
Potential entry scenarios include:
- Same crystal form: highest patent risk and likely direct infringement exposure.
- Different polymorph: possible design-around, but subject to separate patents and regulatory proof.
- Amorphous or solvate form: potentially outside this patent but may introduce stability or manufacturing problems.
- Alternative formulation: may avoid claims 9-11 but not claim 8 if it contains the patented crystal.
- Post-expiration launch: lower patent risk, subject to other unexpired remibrutinib patents and regulatory exclusivities.
No biosimilar pathway applies to this molecule.
What licensing or settlement issues are visible?
The patent’s commercial owner is associated with the Novartis remibrutinib program. No widely reported license, covenant-not-to-sue, Paragraph IV settlement or authorized-generic agreement is established for US Patent 9,796,721 in the conventional public record.
A licensing review should distinguish:
- ownership of the patent;
- ownership of the remibrutinib development program;
- rights transferred under collaboration agreements;
- manufacturing licenses;
- territory-specific rights; and
- any future settlement involving an ANDA or 505(b)(2) applicant.
Patent assignment records and SEC disclosures are more reliable for ownership and transaction analysis than publication metadata alone (U.S. Patent and Trademark Office, n.d.; Novartis AG, n.d.).
Key Takeaways
- US Patent 9,796,721 is a polymorph patent for an anhydrous crystalline form of remibrutinib.
- Claim 1 requires five specific XRPD reflections within ±0.2° 2θ.
- Claims 2 through 7 provide narrower diffraction, anhydrate and measurement-condition limitations.
- Claim 8 covers pharmaceutical compositions containing the claimed crystal form.
- Claims 9 through 11 target compositions with specified extragranular acidulants, particularly alginic acid and its sodium or potassium salts.
- Claims 12 through 17 cover BTK-inhibition methods using the claim 8 composition for selected B-cell malignancies.
- The principal design-around strategy is development of a different polymorph, hydrate, solvate or amorphous form.
- Remibrutinib is a small molecule, so biosimilar rules do not apply.
- No conventional Paragraph IV dispute is established in the public record for this patent.
- The patent’s commercial value depends heavily on whether the claimed anhydrous form is the development and eventual commercial form.
- Exact expiration requires the USPTO term calculation, including filing history and patent-term adjustment.
FAQs
Is US Patent 9,796,721 a patent on remibrutinib itself?
No. It is principally a crystal-form patent. A separate compound patent may protect remibrutinib as a chemical entity.
Can a remibrutinib hydrate avoid US Patent 9,796,721?
Potentially. Claims expressly directed to an anhydrous form may not cover a genuine hydrate, but the claim language, specification, prosecution history and other patents must be reviewed.
Does changing the excipient avoid infringement?
Not necessarily. Claim 8 broadly covers a composition containing the claimed crystal form and at least one pharmaceutically acceptable excipient. Changing the excipient may avoid claims 9 through 11 while leaving claim 8 applicable.
Can an XRPD peak at 6.6° satisfy the 6.4° claim limitation?
It may, because the stated tolerance extends to 6.6° 2θ. The complete pattern, measurement conditions, instrument variation and claim construction must be evaluated.
Is a product containing only amorphous remibrutinib covered?
Generally, an entirely amorphous product would not satisfy a claim directed to the specified crystalline form. Mixed or partially crystallized material creates a more complex infringement and testing question.
References
Google Patents. (n.d.). US9796721B2: Crystalline forms of [remibrutinib compound]. https://patents.google.com/patent/US9796721B2/en
Novartis AG. (n.d.). Annual reports and pipeline disclosures. https://www.novartis.com/investors/financial-data/annual-reporting
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/
U.S. Patent and Trademark Office. (n.d.). Patent Center. https://patentcenter.uspto.gov/
U.S. Patent and Trademark Office. (n.d.). Patent term adjustment. https://www.uspto.gov/patents/laws/patent-term-adjustment
